The folding of cellular proteins is inefficient, and the protein folding problem is even more problematic as cells age and encounter stressful conditions. The concentration of misfolded proteins rises even further in non-replicative cells, such as neurons. Therefore, it is not surprising that the most common ?protein conformational diseases? are linked to neurodegeneration, one of which is Alzheimer?s Disease (AD). AD is exemplified by the accumulation of amyloid plaques and neurofibrillary tangles, which are respectively due to Ab and tau. Although the amyloid hypothesis and the cellular effects of aggregated tau are controversial, protein homeostasis?or ?proteostasis??is clearly compromised in AD neurons. Therefore, if the toxicity associated with the accumulation of Ab and tau could be lessened, the tragic consequences and financial burden of AD could be ameliorated. Fortunately, cells surmount a stress response that can rectify toxicity arising from the accumulation of misfolded proteins. One protective factor that is induced under stress is the Hsp70 chaperone. Hsp70 binds and maintains the solubility of misfolded, aggregation-prone proteins. In addition, higher levels of Hsp70 can protect cells from compromised proteostasis. Unfortunately, while higher levels of Hsp70 are temporarily protective, a sustained increase in Hsp70 levels is toxic or requires genetic manipulations that cannot currently be administered to humans. In contrast, if a compound could directly increase Hsp70 chaperone activity without changing its levels, then improved survival of AD neurons might be evident. In 2008, a first-in-class compound that selectively activates Hsp70 function was identified. NMR analysis established the specificity and mechanism of action of the compound. Moreover, this Hsp70 activator reduces toxic levels of a- synuclein, which gives rise to Parkinson?s Disease, as well as an aggregation-prone polypeptide associated with Huntington?s disease. These efforts emerged from a collaboration between the PI and an expert in drug discovery and medicinal chemistry and were independent of the PI?s parent grant from GMS, which focuses instead on a specific proteostatic pathway. The goal of the current project is to: (1) synthesize and characterize more drug-like derivatives of existing Hsp70 chaperone activators, and (2) screen and then establish the mechanism of action of lead compounds in cellular assays that recapitulate the proteotoxic effects associated with AD. To catalyze progress, local AD experts will act as project consultants, and ultimately preclinical lead compounds will be identified for subsequent in vivo studies.